ORCID
https://orcid.org/0000-0002-2140-0690
Date of Award
11-9-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The landscape of cancer research has undergone a profound transformation, transcending traditional tissue-centric viewpoints to embrace a more intricate understanding of cellular origins and molecular drivers. It has become evident that genes and variants implicated in specific cancers extend their influence across a spectrum of cancer types. Our prior work, encompassing an >10K cases from The Cancer Genome Atlas (TCGA) and more than >1K pediatric cases, illuminated the intricate web of germline predisposition variants and genes spanning 33 cancer types. These findings not only contributed to the refinement of guidelines for rare germline variant detection but also enriched the clinical classification of these elusive genetic variations. Here, I extend these approaches to Multiple Myeloma (MM) - a cancer type not covered in the TCGA dataset - uncovering putative predisposition variants and genes that may explain the missing heritability of this disease. This thesis also delves into the molecular differences between germline and somatic mutations at the pan-cancer level, embracing cutting-edge personal proteogenomics. By leveraging the vast wealth of data generated by large-scale cancer genomics projects, we investigate the distinct effects of germline versus somatic mutations on oncogenic processes, enhancing variant prioritization and providing insights into their impact on gene, protein, and post-translational modification (PTM) levels. Finally, I uncover the influence of germline variants in non-cancer cells on tumorigenesis, examined through state-of-the-art single-cell genomics techniques. While previous studies emphasized the significance of rare germline pathogenic variants in cancer predisposition, they lacked the single-cell resolution necessary to understand their role in tumor heterogeneity and the TME, which has implications for targeted therapies and treatment responses. Advances in single-cell omics, such as snRNA-Seq and snATAC-Seq, enable the exploration of clonal structures, expression changes, and the impact of germline variants on cancer clones and non-cancer cells in the TME. Chapter 4 focuses on a breast cancer (BRCA) cohort from the Human Tumor Network Atlas (HTAN) team, employing bulk and single-cell genomic, transcriptomic, and epigenetic approaches to unravel the influence of germline variants on inter- and intra-tumor heterogeneity, tumor development, progression, and the TME. The work presented here collectively advances our understanding of cancer predisposition variants and genes across cancer types through the use of multiomic approaches, with potential to reshape current prevention, diagnosis, and treatment strategies.
Language
English (en)
Chair and Committee
Li Ding
Recommended Citation
Martins Rodrigues, Fernanda, "Shining a Light through a Multiomic Lens on Germline Variants: Patterns and Functional Implications Across Cancer Types" (2023). Arts & Sciences Electronic Theses and Dissertations. 3188.
https://openscholarship.wustl.edu/art_sci_etds/3188